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N-glycosylation of Wnt3 regulates the progression of hepatocellular carcinoma by affecting Wnt/β-catenin signal pathway

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World Journal of Gastrointestinal Oncology 2024年第6期16卷 2769-2780页

作者： Xin-Zhan Zhang Xiao-Chuan Mo Zhu-Ting Wang Rong Sun Da-Quan Sun Department of biochemistry and Molecular Biology&Research Center for Basic medical Sciences Guizhou Medical UniversityGuiyang 550025Guizhou ProvinceChina

BACKGROUND Wnt/FZD-mediated signaling pathways are activated in more than 90%of hepatocellular carcinoma(HCC)cell *** a well-known secretory glycoprotein,Wnt3 can interact with FZD receptors on the cell surface,thereby activating the Wnt/β-catenin signaling ***,the N-glycosylation modification site of Wnt3 and the effect of this modification on the biological function of the protein are still *** To investigate the effect of Wnt3 N-glycosylation on the biological function of HCC *** Site-directed mutagenesis was used to verify the Wnt3 N-glycosylation sites,actinomycin D treatment was used to detect the stability of Wnt3 after site-directed mutation,the binding of the N-glycosylation site-directed mutant Wnt3 to FZD7 was observed by laser confocal microscopy,and the effects of the N-glycosylation site-directed mutation of Wnt3 on the Wnt/β-catenin signaling pathway and the progression of HCC cells were detected by western blot and cell function *** Wnt3 has two N-glycosylation-modified sites(Asn90 and Asn301);when a single site at amino acid 301 is mutated,the stability of Wnt3 is weakened;the binding ability of Wnt3 to FZD7 decreases when both sites are mutated simultaneously;and the level of proteins related to the Wnt/β-catenin signaling pathway is *** proliferation,migration and invasion are also weakened in the case of single 301 site and double-site *** These results indicate that by inhibiting the N-glycosylation of Wnt3,the proliferation,migration,invasion and colony formation abilities of liver cancer cells can be weakened,which might provide new therapeutic strategies for clinical liver cancer in the future.

关键词： Wnt3 N-glycosylation Hepatocellular carcinoma Liver cancer Wnt/β-catenin FZD7

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Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies

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Signal Transduction and Targeted Therapy 2024年第1期9卷 173-210页

作者： Md Entaz Bahar Hyun Joon Kim Deok Ryong Kim Department of biochemistry and Convergence medical Sciences and Institute of medical Science Gyeongsang National UniversityCollege of MedicineJinjuSouth Korea Department of Anatomy and Convergence medical Sciences and Institute of medical Science Gyeongsang National UniversityCollege of MedicineJinjuSouth Korea

Metastatic dissemination of solid tumors,a leading cause of cancer-related mortality,underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis,chemoresistance,and the mechanistic backgrounds of individuals whose cancers are prone to *** most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase(MAPK)pathway,encompassing the RAS–RAF–MAPK kinase(MEK)–extracellular signal-related kinase(ERK)*** kinase is a primary mediator of the MAPK pathway,responsible for the sequential activation of downstream targets,such as MEK and the transcription factor ERK,which control numerous cellular and physiological processes,including organism development,cell cycle control,cell proliferation and differentiation,cell survival,and *** in this signaling cascade are associated with diseases such as *** inhibitors(RAFi)combined with MEK blockers represent an FDAapproved therapeutic strategy for numerous RAF-mutant cancers,including melanoma,non-small cell lung carcinoma,and thyroid ***,the development of therapy resistance by cancer cells remains an important ***,an intracellular lysosome-dependent catabolic recycling process,plays a critical role in the development of RAFi resistance in ***,targeting RAF and autophagy could be novel treatment strategies for RAF-mutant *** this review,we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and ***,we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic ***,this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.

关键词： RAF insight mechanism

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Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

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World Journal of Gastroenterology 2024年第7期30卷 714-726页

作者： Pui-Yin Leung Wenjing Chen Anissa N Sari Poojitha Sitaram Pui-Kei Wu Susan Tsai Jong-In Park Department of biochemistry Medical College of WisconsinMilwaukeeWI 53226United States Department of Surgery Medical College of WisconsinMilwaukeeWI 53226United States

BACKGROUND Pancreatic cancer is a leading cause of cancer-related *** activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug ***,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic *** previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell *** has not been tested for this *** To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell ***Δψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell *** viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive *** synergy between erlotinib and MitoQ was then analyzed using SynergyFinder *** preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line *** Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive *** triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of *** suggested that these drugs synergistically induced tumor cell *** with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each *** Our findings suggest tha

关键词： Pancreatic cancer Erlotinib Mitochondria-targeted ubiquinone Mitochondria Combination therapy

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TRAIL and Celastrol Combinational Treatment Suppresses Proliferation, Migration, and Invasion of Human Glioblastoma Cells via Targeting Wnt/β-catenin Signaling Pathway

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Chinese Journal of Integrative Medicine 2024年第4期30卷 322-329页

作者： QIN Jing-jing NIU Meng-da CHA Zhe GENG Qing-hua LI Yu-lin REN Chun-guang David P.Molloy YU Hua-rong Research Center of Neuroscience School of Basic Medical SciencesChongqing Medical UniversityChongqing(400016)China Laboratory of Developmental Biology Department of Cell Biology and GeneticsSchool of Basic Medical SciencesChongqing Medical UniversityChongqing(400016)China Department of biochemistry and Molecular Biology School of Basic Medical SciencesChongqing Medical UniversityChongqing(400016)China

Objective To investigate the mechanistic basis for the anti-proliferation and anti-invasion effect of tumor necrosis factor-related apoptosis-induced ligand(TRAIL)and celastrol combination treatment(TCCT)in glioblastoma *** Cell counting kit-8 was used to detect the effects of different concentrations of celastrol(0-16µmol/L)and TRAIL(0-500 ng/mL)on the cell viability of glioblastoma cells.U87 cells were randomly divided into 4 groups,namely control,TRAIL(TRAIL 100 ng/mL),Cel(celastrol 0.5µmol/L)and TCCT(TRAIL 100 ng/mL+celastrol 0.5µmol/L).Cell proliferation,migration,and invasion were detected by colony formation,wound healing,and Transwell assays,*** reverse transcription polymerase chain reaction and Western blotting were performed to assess the levels of epithelial-mesenchymal transition(EMT)markers(zona occludens,N-cadherin,vimentin,zinc finger E-box-binding homeobox,Slug,and β-catenin).Wnt pathway was activated by lithium chloride(LiCl,20 mol/L)and the mechanism for action of TCCT was *** Celastrol and TRAIL synergistically inhibited the proliferation,migration,invasion,and EMT of U87 cells(P<0.01).TCCT up-regulated the expression of GSK-3β and down-regulated the expression of β-catenin and its associated proteins(P<0.05 or P<0.01),including c-Myc,Cyclin-D1,and matrix metalloproteinase(MMP)-*** addition,LiCl,an activator of the Wnt signaling pathway,restored the inhibitory effects of TCCT on the expression of β-catenin and its downstream genes,as well as the migration and invasion of glioblastoma cells(P<0.05 or P<0.01).Conclusions Celastrol and TRAIL can synergistically suppress glioblastoma cell migration,invasion,and EMT,potentially through inhibition of Wnt/β-catenin *** underlies a novel mechanism of action for TCCT as an effective therapy for glioblastoma.

关键词： celastrol Chinese medicine tumor necrosis factor-related apoptosis-induced ligand glioblastoma β-catenin Tripterygium wilfordii

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Unlocking new potential of clinical diagnosis with artificial intelligence:Finding new patterns of clinical and lab data

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World Journal of Diabetes 2024年第3期15卷 308-310页

作者： Pradeep Kumar Dabla Department of biochemistry Govind Ballabh Pant Institute of Postgraduate Medical Education and ResearchDelhi 110002India

Recent advancements in science and technology,coupled with the proliferation of data,have also urged laboratory medicine to integrate with the era of artificial intelligence(AI)and machine learning(ML).In the current practices of evidencebased medicine,the laboratory tests analysing disease patterns through the association rule mining(ARM)have emerged as a modern tool for the risk assessment and the disease stratification,with the potential to reduce cardiovascular disease(CVD)*** are the well recognised leading global cause of mortality with the higher fatality rates in the Indian population due to associated factors like hypertension,diabetes,and lifestyle ***-driven algorithms have offered deep insights in this field while addressing various challenges such as healthcare systems grappling with the physician *** medicine,well driven by the big data necessitates the integration of ML techniques and high-quality electronic health records to direct the meaningful *** technological advancements enhance the computational analyses for both research and clinical *** plays a pivotal role by uncovering meaningful relationships within databases,aiding in patient survival prediction and risk factor *** potential in laboratory medicine is vast and it must be cautiously integrated while considering potential ethical,legal,and privacy ***,an AI ethics framework is essential to guide its responsible *** AI algorithms with existing lab practices,promoting education among healthcare professionals,and fostering careful integration into clinical settings are imperative for harnessing the benefits of this transformative technology.

关键词： Laboratory medicine Artificial intelligence Machine learning Association rule mining Cardiovascular diseases

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Insufficient TRPM5 Mediates Lipotoxicity-induced Pancreaticβ-cell Dysfunction

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Current medical Science 2024年第2期44卷 346-354页

作者： Kai-yuan WANG Shi-mei WU Zheng-jian YAO Yun-xia ZHU Xiao HAN Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing 211166China

Objective:While the reduction of transient receptor potential channel subfamily M member 5(TRPM5)has been reported in islet cells from type 2 diabetic(T2D)mouse models,its role in lipotoxicity-induced pancreaticβ-cell dysfunction remains *** study aims to study its ***:Pancreas slices were prepared from mice subjected to a high-fat-diet(HFD)at different time points,and TRPM5 expression in the pancreaticβcells was examined using immunofluorescence ***-stimulated insulin secretion(GSIS)defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate(Palm).Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm,and the TRPM5 expression was detected using qRT-PCR and Western ***-induced GSIS defects were measured following siRNA-based Trpm5 *** detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5(Ad-Trpm5).Results:HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic *** reduced TRPM5 protein expression in a time-and dose-dependent manner in MIN6 *** also inhibited TRPM5 expression in primary mouse *** of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin *** of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique toβ***:Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreaticβcells both in vivo and in vitro and,in turn,drivesβ-cell dysfunction.

关键词： type 2 diabetes β-cell dysfunction lipotoxicity TRPM5

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Increasing polymer scission rate by tying an overhand knot

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Science China Chemistry 2024年第11期67卷 3498-3499页

作者： Yuheng Hu Jennifer T.Ou Jim Y.Huang Yuanning Feng Department of Chemistry and biochemistry The University of Oklahoma

Similar to the phenomenon of knotted ropes in life, knotted climbing ropes will reduce their strength due to knots. Although computer simulations [1], theoretical speculation[2,3], and intuition [3] suggest that similar processes may occur at the nanoscale, this hypothesis has not been experimentally proven before. With the increasing maturity of molecular recognition and self-assembly, a research communication by Leigh et al. [4] published in Nature Chemistry introduced a molecular overhand knot into a polymer to study its effect on the scission rate of the polymer chain under tension.

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WNT7A promotes tumorigenesis of head and neck squamous cell carcinoma via activating FZD7/JAK1/STAT3 signaling

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International Journal of Oral Science 2024年第1期16卷 85-96页

作者： Qingling Huang Yi Xiao Ting Lan Youguang Lu Li Huang Dali Zheng Department of biochemistry and Molecular Biology School of Basic Medical SciencesFujian Medical UniversityFuzhouChina Fujian Key Laboratory of Oral Diseases School and Hospital of StomatologyFujian Medical UniversityFuzhouChina Department of Preventive Dentistry School and Hospital of StomatologyFujian Medical UniversityFuzhouChina Department of Dentistry The First Affiliated Hospital of Fujian Medical UniversityFuzhouChina

Wnt signaling are critical pathway involved in organ development, tumorigenesis, and cancer progression. WNT7A, a member of the Wnt family, remains poorly understood in terms of its role and the underlying molecular mechanisms it entails in head and neck squamous cell carcinoma (HNSCC). According to the Cancer Genome Atlas (TCGA), transcriptome sequencing data of HNSCC, the expression level of WNT7A in tumors was found to be higher than in adjacent normal tissues, which was validated using Real-time RT-PCR and immunohistochemistry. Unexpectedly, overexpression of WNT7A did not activate the canonical Wnt-β-catenin pathway in HNSCC. Instead, our findings suggested that WNT7A potentially activated the FZD7/JAK1/STAT3 signaling pathway, leading to enhanced cell proliferation, self-renewal, and resistance to apoptosis. Furthermore, in a patient-derived xenograft (PDX) tumor model, high expression of WNT7A and phosphorylated STAT3 was observed, which positively correlated with tumor *** findings underscore the significance of WNT7A in HNSCC progression and propose the targeting of key molecules within the FZD7/JAK1/STAT3 pathway as a promising strategy for precise treatment of HNSCC.

关键词： WNT squamous tumorigenesis

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The gasdermin family:emerging therapeutic targets in diseases

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1905-1937页

作者： Chenglong Zhu Sheng Xu Ruoyu Jiang Yizhi Yu Jinjun Bian Zui Zou Faculty of Anesthesiology Changhai HospitalNaval Medical UniversityShanghai 200433China School of Anesthesiology Naval Medical UniversityShanghai 200433China National Key Laboratory of Immunity&Inflammation Naval Medical UniversityShanghai 200433China d 4 Department of biochemistry and Molecular Biology College of Basic Medical SciencesNaval Medical UniversityShanghai 200433China

The gasdermin(GSDM)family has garnered significant attention for its pivotal role in immunity and disease as a key player in *** recently characterized class of pore-forming effector proteins is pivotal in orchestrating processes such as membrane permeabilization,pyroptosis,and the follow-up inflammatory response,which are crucial self-defense mechanisms against irritants and *** have been implicated in a range of diseases including,but not limited to,sepsis,viral infections,and cancer,either through involvement in pyroptosis or independently of this *** regulation of GSDM-mediated pyroptosis is gaining recognition as a promising therapeutic strategy for the treatment of various *** strategies for inhibiting GSDMD primarily involve binding to GSDMD,blocking GSDMD cleavage or inhibiting GSDMD-N-terminal(NT)oligomerization,albeit with some off-target *** this review,we delve into the cutting-edge understanding of the interplay between GSDMs and pyroptosis,elucidate the activation mechanisms of GSDMs,explore their associations with a range of diseases,and discuss recent advancements and potential strategies for developing GSDMD inhibitors.

关键词： diseases therapeutic immunity

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N-acetylserotonin alleviates retinal ischemia-reperfusion injury via HMGB1/RAGE/NF-κB pathway in rats

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International Journal of Ophthalmology(English edition) 2024年第2期17卷 228-238页

作者： Yu-Ze Zhao Xue-Ning Zhang Yi Yin Pei-Lun Xiao Meng Gao Lu-Ming Zhang Shuan-Hu Zhou Shu-Na Yu Xiao-Li Wang Yan-Song Zhao Department of Ophthalmology Affiliated Hospital of Weifang Medical UniversityWeifang 261031Shandong ProvinceChina School of medical Imaging Weifang Medical UniversityWeifang 261053Shandong ProvinceChina Department of Anatomy Weifang Medical UniversityWeifang 261053Shandong ProvinceChina departments of Orthopedic Surgery Brigham and Women’s HospitalHarvard Medical SchoolBostonMA 02115USA

AIM:To observe the effects of N-acetylserotonin(NAS)administration on retinal ischemia-reperfusion(RIR)injury in rats and explore the underlying mechanisms involving the high mobility group box 1(HMGB1)/receptor for advanced glycation end-products(RAGE)/nuclear factor-kappa B(NF-κB)signaling ***:A rat model of RIR was developed by increasing the pressure of the anterior chamber of the *** male Sprague Dawley were randomly divided into five groups:sham group(n=8),RIR group(n=28),RIR+NAS group(n=28),RIR+FPS-ZM1 group(n=8)and RIR+NAS+FPS-ZM1 group(n=8).The therapeutic effects of NAS were examined by hematoxylin-eosin(H&E)staining,and retinal ganglion cells(RGCs)*** expression of interleukin 1 beta(IL-1β),HMGB1,RAGE,and nod-like receptor 3(NLRP3)proteins and the phosphorylation of nuclear factorkappa B(p-NF-κB)were analyzed by immunohistochemistry staining and Western blot *** expression of HMGB1 protein was also detected by enzyme-linked immunosorbent assay(ELISA).RESULTS:H&E staining results showed that NAS significantly reduced retinal edema and increased the number of RGCs in RIR *** NAS therapy,the HMGB1 and RAGE expression decreased significantly,and the activation of the NF-κB/NLRP3 pathway was antagonized along with the inhibition of p-NF-κB and NLRP3 protein ***,NAS exhibited an anti-inflammatory effect by reducing IL-1β*** inhibitory of RAGE binding to HMGB1 by RAGE inhibitor FPS-ZM1 led to a significant decrease of p-NF-κB and NLRP3 expression,so as to the IL-1βexpression and retinal edema,accompanied by an increase of RGCs in RIR ***:NAS may exhibit a neuroprotective effect against RIR via the HMGB1/RAGE/NF-κB signaling pathway,which may be a useful therapeutic target for retinal disease.

关键词： retinal diseases retinal ischemia—reperfusion injury N-acetylserotonin high mobility group box 1 receptor for advanced glycation end-products nuclear factor-κB rats

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